OBJECTIVE- Retinol binding protein-4 (RBP4), a novel protein secreted mainly by adipose tissue, has been associated with insulin resistance in obese subjects and in individuals with type 2 diabetes mellitus (T2DM). We examined the relationship between plasma RBP4 levels, expression of RBP4 in skeletal muscle and adipose tissue, and insulin sensitivity in Mexican Americans with varying degrees of obesity and glucose tolerance. RESEARCH DESIGN AND METHODS- Seventy two; 16 lean normal-glucose-tolerant (NGT), 17 obese NGT, 39 subjects with impaired fasting glucose/impaired glucose tolerance/T2DM] received an oral glucose tolerance test (OGTT) and euglycemic hyperinsulinemic clamp. Insulin secretion was measured as insulinogenic index (I/G) during OGTT. In a subset of subjects, hepatic glucose production was measured by of 3-[³H] glucose infusion, and biopsies of the vastus lateralis muscle and subcutaneous adipose tissue were obtained under basal conditions and quantitative RT-PCR was performed to measure the RBP4 mRNA gene expression. RESULTS- Plasma RBP4 was significantly elevated in IGT/T2DM compared to NGT lean or obese subjects. Plasma RBP4 levels correlated with 2-hour glucose, triglycerides and HbA1c. There was no association between RBP4 levels and whole body insulin sensitivity measured with either the euglycemic insulin clamp or OGTT, basal hepatic glucose production rates and the hepatic insulin resistance index. There was no correlation between plasma RBP4 levels and indices of insulin secretion. RBP4 mRNA expression in skeletal muscle was similar in lean NGT subjects, obese NGT subjects and T2DM subjects. There was no difference in RBP4 mRNA expression in adipose tissue between lean and obese NGT subjects or between NGT and T2DM individuals. CONCLUSIONS- Plasma RBP4 levels are elevated in T2DM and associated with impaired glucose tolerance, but not associated with obesity or insulin resistance or impaired insulin secretion in Mexican Americans.